Various methods and compositions for targeted cleavage of genomic DNA have been described. Such targeted cleavage events can be used, for example, to induce targeted mutagenesis, induce targeted deletions of cellular DNA sequences, and facilitate targeted recombination at a predetermined chromosomal locus. See, for example, United States Patent Publications 20030232410; 20050208489; 20050026157; 20050064474; 20060188987; 2008015996, and International Publication WO 2007/014275, the disclosures of which are incorporated by reference in their entireties for all purposes. See, also, Santiago et al. (2008) Proc Nat'l Aced Sic USA 105:5809-5814; Perez et al. (2008) Nat Biotechnol 26:808-816 (2008).
For HIV, the most important co-receptors in vivo are CCR5, a 7-transmembrane chemokine receptor, and CXCR4 (a CXC chemokine receptor). See, e.g., Feng et al. (1996) Science 272:872-877; Deng et al. (1996) Nature 381:661-666; Schuitemaker et al. (1999) J. Virol. 73:5373-5380. HIV type 1 (HIV-1) strains that use only CCR5 (R5 viruses), predominate during the early stages of infection and are critical for transmission (Schuitemaker et al. (1992) J. Virol. 66:1354-1360; van't Wout et al. (1994) J. Clin. Invest. 94:2060-2067). Although R5 viruses generally persist in late stage disease, viruses that can use CXCR4, either exclusively (X4 viruses) or in addition to CCR5 (R5X4 viruses), emerge in approximately 50% of subtype B-infected individuals (Connor et al. (1997) J. Exp. Med. 185:621-628; Karlsson et al. (1994) J. Clin. Microbiol. 32:364-370). This co-receptor switch is associated with a more rapid decline in peripheral blood CD4+ T cells and a faster progression to AIDS (Richman, D. et al. (1994) J. Infect. Dis. 169:968-974).
Thus, there remains a need for compositions that knock-out CXCR4 for treatment and prevention of CXCR4-tropic HIV infection.